This invention relates to processes suitable for the large-scale preparation of enantiomerically-enriched cyclic phosphines, especially those useful as ligands in asymmetric hydrogenation catalysts.
Chiral cyclic phosphines are useful ligands for asymmetric catalysis. In particular, chiral ligands of the DuPHOS and BPE series, respectively represented by formulae (1) and (2) 
wherein R1 and R2 are typically C1-6 linear or branched alkyl, and enantiomeric forms thereof, can be used to prepare rhodium and ruthenium complexes, which are effective and versatile catalysts for asymmetric hydrogenation of a diverse range of substrate types. For a review, see Burk et al, Pure Appl. Chem. (1996) 68:37-44.
Such catalysts are eminently suitable for industrial applications, especially for the provision of chiral pharmaceutical intermediates in high enantiomeric purity. For this purpose, and in other industrial applications such as flavour and fragrance fine chemicals, the development of manufacturing processes requires in turn large amounts of a ligand (1) or (2), e.g. in kilogram quantity or greater. Thus, there is a requirement for efficient and scaleable methods for synthesis of such ligands.
As described in U.S. Pat. No. 5,532,395 and WO 93/01199, an established procedure for the preparation of DuPHOS and BPE ligands entails the reaction of a bis(primary)phosphine with a 1,4-alkanediol cyclic sulphate mediated by a strong base capable of deprotonating a Pxe2x80x94H bond, typically n-butyllithium. 2 Equivalents of the cyclic sulphate, optionally in a small excess, and at least 4 equivalents of base are required. A representative process of this type, for the preparation of (S,S)-methyl DuPHOS, is shown in the following scheme: 
The literature procedure stipulates that reactants should be added to the reaction vessel in the following order:
(a) 2 equivalents of n-butyllithium are added to a solution of 1,2-bis(phosphino)benzene in THF at 20-30xc2x0 C., ostensibly to generate dilithium 1,2-bis(phosphido)benzene;
(b) after 1-1.5 h, a solution of (R,R)-1,4-hexanediol cyclic sulphate (2 equivalents) in THF is added to the resultant mixture;
(c) after a further 1 h, a second aliquot of n-butyllithium (2.2-2.3 equivalents) is added;
(d) at the end of the reaction, work-up comprises addition of methanol and successive cycles of filtration, solvent washing and solvent evaporation, with progressive reduction in solvent polarity (diethyl ether, then pentane). An aqueous work-up is avoided.
The protocol described above is well suited to laboratory-scale synthesis of a ligand of formula (1) or (2), typically to prepare 1-10 g quantities. At this scale, operating parameters such as temperature, reaction duration, request stoichiometry, and exclusion of air and moisture are easily controlled. However, on a larger scale, it has been found that it is more difficult to achieve the same yield of the ligand, and that side-reactions can hinder ligand purification. This may be a consequence of one or more factors, such as inadequate exclusion of air and moisture in a manufacturing plant vessel, and, in order to maintain temperature control, prolonged duration of reagent addition and overall reaction time. Without wishing to be bound by theory, anionic species generated in step (a) have a longer residence time, and may be consumed by reaction with the solvent (TBF). Thus yields in steps (b) and (c) are reduced.
For example, U.S. Pat. No. 5,532,395 describes the preparation of (S,S)-methyl DUPHOS from 0.8 g of 1,2-bis(phosphino)benzene, in which a yield of 78% is achieved. In contrast, when scaling up this procedure by a factor of 75, using 60 g of 1,2-bis(phosphino)benzene, the yield of methyl DuPHOS can fall to below 30%. Overall, such lowering of yield has an adverse effect on the economics of the process.
Wilson and Pasternak, Synlett 4:199-200 (April 1990), discloses the preparation of chiral phosphines for use in an asymmetric Staudinger reaction.
U.S. Pat. No. 5,399,771 discloses the preparation of BINAP using diphenylphosphine, an amine base and a nickel catalyst.
GB-A-2262284 discloses the preparation of tertiary phosphines.
This invention is based on the discovery that an efficient, high-yielding preparation of a cyclic phosphine is facilitated by a new mode of reagent addition. More specifically, a process for the preparation of a cyclic phosphine from the corresponding primary phosphine and a bifunctional alkylating agent, wherein alkylation, and displacement of each functional group, occurs in the presence of a strong base, comprises adding the strong base, in an amount sufficient for cyclisation, to a preformed mixture or reaction product of the primary phosphine and alkylating agent.
It is surprising that high yields are achieved in this process, given the potential for side-reactions, which an individual of ordinary skill in the art might predict. In particular, the bifunctional alkylating agent is susceptible to xcex2-elimination by reaction with a strong base. However, in practice, xcex2-elimination is not observed as a major reaction pathway. Also noteworthy is the fact that this process allows the preparation of phosphines bearing very hindered functional groups such as tert-butyl through substitution at neopentyl-like centres of the alkylating agent.
In addition to improvements in yield and product purity, simplicity of process operation is another benefit when compared to the original protocol, since all of the base required to mediate the reaction is added in a single operation, after the reaction vessel has been charged with all other reactants. Moreover, it is found that, in general, cyclic phosphines withstand aqueous work-up, which is advantageous in terms of material transfer/handling, allowing convenient separation of ionic species (salts, etc) from the product.
The process of this invention preferably comprises the addition of at least 2 m equivalents of a strong base to a mixture or reaction product of the primary phosphine and at least m equivalents of the bifunctional alkylating agent. The cyclic phosphine, the primary phosphine and the bifunctional alkylating agent that are used in this invention are preferably respectively of formula (3), (4) and (5) 
In formulae (3)-(5), R1 and R2 are independently H, alkyl, cycloalkyl, aryl, aralkyl or alkaryl, provided that both are not H, R3 is aryl, alkyl, cycloalkyl, aralkyl, alkaryl, or an organometallic residue such as ferrocenyl; m is 1 or 2; n is in the range 1-4; and X and X1 are the same or different nucleofugal leaving groups, optionally linked to form a ring. The cyclic phosphine ring in (3) may optionally form part of a fused polycyclic ring system.
Any base capable of effecting complete deprotonation of a Pxe2x80x94H bond is suitable for use in the novel process. Commercially available organolithium bases are ideal for this purpose and alkyllithiums are preferred, especially n-butyllithium and sec-butyllithium. A variety of solvents may be used, particularly ethereal solvents such as tetrahydrofuiran (TBF), diglyme, diethyl ether or t-butyl methyl ether. THF is the preferred solvent, and hydrocarbon solvents, e.g. hexanes, such as might be used for dissolution of an organolithium base, are compatible as cosolvents.
A preferred embodiment of the present invention is a process for preparation of enantiomerically-enriched ligands of formula (3), from enantimerically-enriched alkylating agents of formula (5). The degree of enrichment is typically at least 70% ee, preferably at least 80% ee, more preferably at least 90% ee, and most preferably at least 95% ee.
Further, it is preferred that R1 and R2 are orientated trans to one another. Usually, although not necessarily, R1 and R2 are the same. This encompasses ligands of the DuPHOS (1) and BPE (2) series and monophosphospholane variants thereof. Further, it includes the use of phosphetane ligands, as disclosed in WO 98/02445, of formula (6) 
For monophosphetanes (6) wherein Y=Ph, the process of the present invention is especially advantageous, since transfer of a solution of lithiated phenylphosphine between reaction vessels is avoided, thereby reducing the exposure risk to this noxious and foul-smelling substance.
In another embodiment of the present invention, the preparation of novel ferrocenyl bisphosphetanes of formula (7) 
and opposite enantiomers thereof, wherein R1 and R2 are linear or branched alkyl, demonstrates functional group compatibility. In the case of compounds of formula (7) wherein R1=R2=t-Bu, controlled nucleophilic substitution at neopentyl-like centres may be achieved.
For preparation of ligands of formulae (1), (2), (6) and (7), and related compounds, preferred bifunctional alkylating agents are those prepared from the corresponding single enantiomer 1,3- and 1,4-diols. Cyclic sulphate derivatives are preferred, although bis(aryl)sulphonates or bis(alkyl)sulphonates, such as ditosylates, can be used with equal facility. 1,4-Diol precursors of phospholane ligands (1) and (2) can be prepared either by electrochemical Kolbe coupling [see Burk et al, Organometallics (1990) 9:2653] or more conveniently via biocatalytic resolution of racemic diols [Berens, Proceedings of Chiral Europe 1996 (Spring Innovations Ltd.), p. 13]. 1,3-Diol precursors of phosphetanes (6) are easily accessible by asymmetric hydrogenation of the corresponding 1,3-diketones (for lead references, see WO 98/02445).